Chewable enteric coated aspirin tablets

ABSTRACT

The invention relates to a tablet capable of being chewed or disintegrated in the oral cavity, which comprises an enteric coated aspirin active ingredient, and preferably a lightly compressed matrix comprising directly compressible carbohydrate(s) and at least one sweetener.

The present invention relates to a chewable or disintegrative tabletcomprising enteric coated aspirin particles, preferably compressed intotablet form using dextrose monohydrate, and sucralose.

BACKGROUND OF THE INVENTION

Pharmaceuticals intended for oral administration are typically providedin solid form as tablets, capsules, pills, lozenges, or granules.Tablets are swallowed whole, chewed in the mouth, or dissolved in theoral cavity. Chewable or disintegrative tablets are often employed inthe administration of pharmaceuticals where it is impractical to providea tablet for swallowing whole, for instance with pediatric patients. Inaddition, with chewable tablets, the act of chewing helps to break upthe tablet particles as the tablet disintegrates and may increase therate of absorption by the digestive tract.

Workers in the field continue to try to improve the flavor and mouthfeelof chewable tablets and other comestibles. For instance, U.S. Pat. No.4,327,076 to Puglia et al. relates to a chewable tablet formed ofparticles of active ingredient isolated from other ingredients of thetablet by admixing those particles with particles formed of an ediblefat or oil absorbed on a fat-absorbing material, such asmicrocrystalline cellulose. The particles are blended with one or moretablet bonders, such as dextrose monohydrate. In addition, the tabletmay also comprise other conventional ingredients, such as sweeteners.

U.S. Pat. No. 4,327,077 to Puglia et al. also relates to a chewabletablet. The tablet comprises particles of a recrystallized fattymaterial such as chocolate, a bulking material such as sugar or anactive ingredient bound up in the particles of recrystallized fattymaterial, and a direct compaction vehicle that may be dextrosemonohydrate.

PCT Application No. WO 99/47126 discloses compressed tablets capable ofrapidly dissolving in aqueous solutions, comprising at least onenon-saccharide water soluble polymer such as polyvinylpyrrolidone,optionally a saccharide of low moldability such as glucose, optionally asaccharide of high moldability such as maltose, sorbitol or a mixturethereof, and optionally a sweetener such as sucralose. These tablets areprepared by wet granulation, specifically a) granulating a formulationcomprising the non-saccharide, water soluble polymer and activeingredient using no organic solvents, (b) compressing this into tabletform, (c) humidifying the tablet by exposing it to an aeratedenvironment having at least about 50 to 100% relative humidity, and (d)drying the tablet.

Chewable tablets are known. U.S. Pat. No. 5,489,436 describes a chewabletablet made from a coated medicament wherein the coating comprises amixture of dimethylaminoethyl methacrylate, a neutral methacrylic acidester and a cellulose ester. The coating is described as a reverseenteric coating, which is not water soluble in non-acidic conditions butis soluble in acidic conditions. U.S. Pat. No. 4,851,226 describes achewable medicament tablet made from coated granules of medicamentwherein the coating on said granules comprises a blend of celluloseacetate or cellulose acetate butyrate and polyvinyl pyrrolidone. U.S.Pat. No. 4,800,087 describes a microencapsulating polymer for coating apharmaceutical core that is capable of taste-masking the activecompound. The polymer is described as maintaining its integrity whentabletted and/or chewed and can provide immediate release of the activecompound in the stomach, or can release the active ingredient in theupper intestinal tract or in a sustained release fashion. U.S. Pat. No.4,970,081 describes rapidly disintegrating aspirin tablets wherein theaspirin granules have been coated to provide a zero order release of theactive ingredient.

It is also known that pharmaceutically active ingredients can beprovided with enteric coatings. Providing enteric coatings on the activeingredient for aspirin, however, presents a number of unique challengesdue to potential hydrolysis of the active to produce free salicylicacid. Several patents have been published that allegedly describestabilized enteric-coated aspirin compositions, such as U.S. Pat. No.4,900,559, which describes a stabilized enteric coated aspirin granulesproduct prepared by commingling the enteric coated aspirin granule withglutamic acid hydrochloride. U.S. Pat. No. 5,068,110 allegedly improvesthe stability of an enteric-coated dosage form through the applicationof higher levels of coatings or by the application of higher levels ofcoatings in combination with the use of a protective coating.

Acid-labile actives, enteric coated and non-enteric coated, have beenformulated as orally disintegratable tablets. For example, published PCTapplication WO 03/007917 describes a dosage form for enteric coatedproton pump inhibitors in the form of a multi-particulate tablet thatdisintegrates in the mouth. Published U.S. Patent application2004/0110661 describes a rapidly disintegrating tablet for acid-labileactive ingredients. The tablet is described as comprising a plurality ofindividual active ingredient units together with excipients, wherein theacid-labile active is present in individual active ingredient units in amatrix composed of a mixture of a solid paraffin and one or more of afatty alcohol, triglycerides and fatty acid ester. Published U.S. Patentapplication 2002/0142034 describe an orally disintegrable tablet thatcomprises fine granules having an average particle diameter of 400 μm orless.

There remains a need for a pharmaceutical product that can be chewed orthat disintegrates in the mouth, which contains an enteric-coatedaspirin active ingredient.

SUMMARY OF THE INVENTION

The present invention provides a tablet capable of being chewed ordisintegrated in the oral cavity prior to swallowing, comprisingenteric-coated aspirin particles, and preferably a matrix comprisingdirectly compressible sugars or sugar-alcohols and high intensitysweetener, said tablet containing less than 5% fat and said matrix beingsubstantially free of non-saccharide, water soluble polymeric binders.

DETAILED DESCRIPTION OF THE INVENTION

The tablet is made from a mixture comprising enteric-coated aspirinparticles, preferably using directly compressible sugars orsugar-alcohols, together with high intensity sweeteners, and preferablythe tablet has a sweetness index greater than about 1.0.

The enteric-coated aspirin is present in the tablet in a therapeuticallyeffective amount, which is an amount that produces the desiredtherapeutic response upon oral administration and can be readilydetermined by one skilled in the art. In determining such amounts, theparticular active ingredient being administered, the bioavailabilitycharacteristics of the active ingredient, the dose regime, the age andweight of the patient, and other factors must be considered, as known inthe art.

The active ingredient is in form of particles, typically have an averageparticle size of about 1 micron to about 2000 microns. In oneembodiment, the active ingredient particles are crystals having anaverage particle size of about 1 micron to about 1500 microns, e.g. fromabout 20 to about 1000 microns. In another embodiment, the activeingredient particles are granules or pellets having an average particlesize of about 50 microns to about 2000 microns, e.g. about 50 microns toabout 1000 microns, or about 100 microns to about 800 microns. As usedherein, granules or pellets are typically agglomerates comprising aplurality of active ingredient crystals, and optionally excipients suchas binders.

In one embodiment, the active ingredient is in the form of a largecrystal, and typically has an average particle size from about 20 toabout 1000 microns. Preferably, the active ingredient has an averageparticle size from about 50 to about 700 microns, and more preferablythe active ingredient has an average particle size from about 100 toabout 500 microns.

The thickness of the enteric coating on the active ingredient-containingcore particle is typically from about 1 micron to about 20 microns, e.g.from about 2 microns to about 15 microns or from about 4 to about 9microns.

Particles coated with an enteric coating, in a dried state, generallycontain the enteric coating in an amount, based upon the total weight ofparticle and the enteric coating, from about 1 percent to about 50percent, e.g. from about 15 percent to about 25 percent. The exactproportions of the coating to the active ingredient can vary dependingupon, for example, the level of taste masking required. In embodimentsemploying a granulated particle, such as a rotogranulated particle, theactive ingredient will constitute from about 5 to about 90 weightpercent of the particle, with the remainder being the binder or filler.Suitable binders for the granulated particles include polyvinylpyrrolidone, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, andother pharmaceutically acceptable polymers. Fillers suitable for use insuch granulated particles include lactose, confectioner's sugar,mannitol, dextrose, fructose, other pharmaceutically acceptablesaccharide and microcrystalline cellulose.

In the practice of the present invention the enteric coating solutionused to form the enteric coating layer on the tablets will comprise awater-soluble or water dispersible film forming enteric polymerdissolved or dispersed in an aqueous vehicle. A number of such filmforming enteric polymers are known in the prior art that will serve thepresent purposes. At least three aqueous enteric polymer coatings arecommercially available, Eudragit L30D (methacrylic acid-methacrylic acidester copolymer marketed by Rohm-Haas GmBH, West Germany), Aquateric, acellulose acetate phthalate-containing product marketed by FMCCorporation, Philadelphia, Pa. and Coateric (a polyvinyl acetatephthalate-based product marketed by Colorcon, Inc., West Point, Pa.).These will have conventional solubility characteristics of entericpolymers i.e. they will be insoluble in acid but will be soluble in aneutral-to-nearly alkaline medium.

One class of enteric polymers that are particularly suitable for thepurpose of this invention is water-soluble or water dispersible acrylicresins. Of special interest in this regard is a polymer sold under thetrade name Eudragit L30D. This is a copolymer that is anionic incharacter and based on polymethacrylic acid and acrylic acid esters.This is described by the formula:

wherein: n is a number,

R is H or CH₃ and R₁ is CH₃ or C₂H₅,

the ratio of free carboxyl group to ester groups is 1:1 and the meanmolecular weight of the polymer is about 250,000.

The coating solution used to prepare the enteric coating layer on thetablets according to this invention may contain the enteric polymerformed from a high concentration aqueous system. In general this willamount to about 20% to about 35% by weight of enteric polymer based onthe total weight of the coating solution with the preferred range beingfrom about 25% to about 32% on the same weight basis, most preferablyabout 30%. Another important feature of this invention is therequirement for having a large weight gain of more than 25%, preferablymore than 30% weight gain. The coating solution can further containconventional plasticizers such as triethyl citrate, diethyl phthalate,tributyl citrate, triacetin, dibutyl phthalate, dibutyl sebecate,Myvacet 940, polyethylene glycol and other commonly used plasticizers asmay be suitable for particular enteric polymers can be used.

The active ingredient is contained in a matrix comprising one or moreedible carbohydrates such as dextrose monohydrate, mannitol, lactose,sucrose, erythritol, sorbitol, xylitol and other commonly usedcarbohydrates suitable for making tablets capable of being chewed ordisintegrated in the oral cavity prior to swallowing. The amount ofedible carbohydrate in the tablet is typically about 15 to about 90% byweight, preferably about 25 to about 85% by weight, and more preferablyabout 30 to about 75% by weight of the total weight of the tablet. Thematrix also comprises one or more high intensity sweeteners.

The dosage form of the invention is a chewable or orally disintegratabletablet wherein the active ingredient is contained in a matrix comprisingconventional, pharmaceutically acceptable excipients, such as fillers,conventional dry binders, sweeteners, disintegrants, and lubricants suchas, for example, stearic acid, magnesium stearate, and mixtures thereof.Suitable fillers for chewable or orally disintegratable tablets includewater-disintegratable, edible carbohydrates such as, for example,sugars, sugar alcohols, starch hydrolysates, and mixtures thereof.Examples of suitable sugars include, but are not limited to dextrose,sucrose, maltose, and lactose. Examples of suitable sugar alcoholsinclude, but are not limited to mannitol, sorbitol, maltitol, xylitol,and erythritol. Examples of suitable starch hydrolysates include, butare not limited to, dextrins and maltodextrins.

In one embodiment, the water-disintegratable, compressible carbohydratemay be selected from dextrose monohydrate, mannitol, sorbitol, xylitol,and mixtures thereof. In embodiments in which a water-disintegratablecompressible carbohydrate is employed as a filler, it is typicallypresent at a level from, based upon the total weight of the dosage form,from about 40 to about 90 percent, e.g. from about 50 to about 80percent.

The matrix may also incorporate pharmaceutically acceptable adjuvants,including, for example, preservatives, flavors such as, for example,orange and/or vanilla, acidulants, glidants, surfactants, and coloringagents such as, for example, FD&C yellow. However, the matrix preferablycomprises no more than, based upon the total weight of the dosage form,about 25 weight % of such optional auxiliary ingredients.

The amount of edible carbohydrate in the tablet is typically about 15 toabout 90% by weight, e.g. about 25 to about 85% by weight, say about 30to about 75% by weight of the total weight of the tablet.

Intense sweetener compounds suitable for use herein includewater-soluble artificial sweeteners such as 1,2-benzisothiazol-3(2H)-one 1,1-dioxide (saccharin and its salts), cyclohexylsulfamic acid(cyclamate and its salts), and the potassium salt of6-methyl-1,2,3-oxathiazin-4 (3H)-one-2,2-dioxide (Acesulfame-K, acommercially available product from Hoechst Celanese Corporation,Somerville, N.J.), proteins such as thaumatin (Talin, a commerciallyavailable product of Tate & Lyle Products, Reading, United Kingdom),chlorodeoxysugar derivatives (such as Sucralose, a commerciallyavailable product of Tate & Lyle), and dipeptides such asN-L-alpha-aspartyl-L-phenylalanine I-methyl ester (Aspartame, acommercially available product of the Nutrasweet Company, Deerfield,Ill.) and L-alpha-aspartyl-D-alanineN-(2,2,4,4-tetramethyl-3-thietanyl)amide (Alitame, a commerciallyavailable product of Pfizer, New York, N.Y.), and dihydrochalcones . . .. The amount of high intensity sweetener in the tablet is typicallyabout 0 to about 20% by weight, preferably about 0.01 to about 5% byweight, and more preferably about 0.1 to about 3% by weight of the totalweight of the tablet.

In a preferred embodiment, the chewable or orally disintegratable tabletof the present invention has a sweetness index greater than about 1.0.Sweetness index is an indication of the relative sweetness of a materialwith respect to that of sucrose. Sucrose is used as the standard, with asweetness index of 1.0. Dextrose (glucose) has a sweetness index ofabout 0.6, which is it is about 60% as sweet as sucrose. Sucralose, ahigh intensity sweetener, has a sweetness index of about 600, that is,it is about 600 times as sweet as sucrose. The sweetness index of thetablet can be calculated as a weighted sum of all the sweeteningingredients in the tablet, i.e. the sum of the mass fraction of eachingredient times its sweetness index. Those skilled in the art willrecognize that the presence of a high-intensity sweetener is necessaryin order to make a chewable or orally disintegratable tablet having asweetness index greater than 1.0.

In one particular embodiment, the edible carbohydrate is dextrosemonohydrate and the high intensity sweetener is sucralose. Sucralose,4,1′6′-trichloro-4,1,6′-trideoxy-galactosucrose, is a high intensitysweetener manufactured from sucrose as a starting material. This andother chlorine-substituted sucrose sweeteners are disclosed in BritishPatent No. 1,544,167, and in British Patent Application No. 2,104,063A.In embodiments employing sucralose as the high intensity sweetener, theamount of sucralose in the tablet is typically about 0.005 to about 10%by weight of the total weight of the tablet, preferably about 0.01 toabout 5% by weight, and more preferably about 0.5 to about 2% by weightof the total weight of the tablet. Preferably, the weight ratio ofdextrose monohydrate to sucralose in the tablet is at least about 25:1,more preferably at least about 50:1, most preferably at least about75:1. Preferably, the dextrose monohydrate is present in the tablet indirectly compressible form. That is, the dextrose monohydrate has anaverage particle size of about 100 to about 500 microns, e.g. about 100to about 250 microns, say about 150 to about 200 microns. Such aparticle size is useful to impart the formulation with adequateflowability and compressibility, and with a smooth and creamy mouthfeel.

The amount of edible carbohydrate in the tablet is typically about 15 toabout 90% by weight, preferably about 25 to about 85% by weight, andmore preferably about 30 to about 75% by weight of the total weight ofthe tablet.

The use of directly compressible carbohydrate at these levels enablesthe minimization or elimination of cellulosic dry binders such asmicrocrystalline cellulose from the formula. The avoidance ofmicrocrystalline cellulose improves both the taste and the mouthfeel ofthe resulting tablets. While it may be desirable to use microcrystallinecellulose at relatively low levels in the formulation for itsdisintegrant properties, the higher levels generally used for bindingproperties are not necessary. The amount of microcrystalline cellulosein the tablet is preferably less than about 20% by weight, morepreferably less than about 10% by weight of the tablet, and mostpreferably, the tablet is substantially free of microcrystallinecellulose.

The use of directly compressible carbohydrates at these levelsadvantageously enables the minimization or elimination of fat. Fats aregenerally understood to mean esters of glycerol and fatty acids, whichcan include monoglycerides, diglycerides, and triglycerides. Preferably,the tablet of the present invention contains less than about 5% fat.More preferably, the tablet contains less than about 3% by weight offat, most preferably the tablet contains substantially no fat. Fat-freeformulations are more stable at elevated temperatures, eliminating theneed for specially controlled shipping and storage conditions.Additionally, fats are susceptible to oxidative and chemical hydrolysis,leading to a “rancid” taste and/or odor. This effectively shortens theshelf life of a product. Preferably the melting point of any fats orother oily materials that are included in the composition is greaterthan about 80° F. in order to maintain product stability at elevatedtemperatures during shipping or storage.

In a particularly preferred embodiment of the invention the tablet issubstantially free of tri-glycerides specifically. Triglycerides aremore hydrophobic than mono- and di-glycerides, and are expected tohinder dissolution of the active ingredient. This is undesirable in animmediate release dosage form such as the tablet of this invention.

The tablet may contain other conventional ingredients, such as fillers,conventional dry binders, other sweeteners, disintegrants, andlubricants. The mixture may also incorporate pharmaceutically acceptableadjuvants, including, for example, preservatives, flavors, acidulantsantioxidants, glidants, surfactants, and coloring agents. However, thetablet preferably comprises no more than about 25 weight % of suchoptional auxiliary ingredients.

The tablet may be made in any manner, and a variety of tableting methodsare known in the art. Conventional methods for tablet production includedirect compression (“dry blending”), dry granulation followed bycompression, and wet granulation followed by drying and compression.Other methods include the use of compacting roller technology such as achilsonator or drop roller, or molding, casting, or extrusiontechnologies. All of these methods are well known in the art, and aredescribed in detail in, for example, Lachman, et al., The Theory andPractice of Industrial Pharmacy, Chapter 11, (3^(rd) Ed. 1986).

Preferably the tablets are formed by the direct compression method,which involves directly compacting a blend of the enteric-coatedaspirin, dextrose monohydrate, sucralose, and any other appropriateoptional ingredients. After blending, a pre-determined volume ofparticles is filled into a die cavity of a rotary tablet press, whichcontinuously rotates as part of a “die table” from the filling positionto a compaction position. The particles are compacted between an upperpunch and a lower punch to an ejection position, at which the resultingtablet is pushed from the die cavity by the lower punch and guided to anejection chute by a stationary “take-off” bar. The direct compressionprocess enables the minimization or elimination of water-soluble,non-saccharide polymeric binders such as polyvinyl pyrrolidone,alginates, hydroxypropyl cellulose, hydroxypropylmethylcellulose,hydroxyethylcellulose, and the like, which can have an adverse effect ondissolution.

Preferably, tableting is carried out such that the tablet is relativelysoft. The hardness of the tablet is preferably up to about 15 kilopondsper square centimeter (kp/cm²). More preferably, the hardness of thetablet is in the range of about 1 to 8 kp/cm², most preferably about 2to 6 kp/cm². Hardness is a term used in the art to describe thediametral breaking strength as measured by conventional pharmaceuticalhardness testing equipment, such as a Schleuniger Hardness Tester. Inorder to compare values across different size tablets, the breakingstrength is normalized for the area of the break (which may beapproximated as tablet diameter times thickness). This normalized value,expressed in kp/cm², is sometimes referred in the art as tablet tensilestrength. A general discussion of tablet hardness testing is found inLeiberman et al., Pharmaceutical Dosage Forms—Tablets, Volume 2, 2^(nd)ed., Marcel Dekker Inc., 1990, pp. 213-217, 327-329.

In another embodiment the tablet may be made using a process designed toproduce a freeze-dried foam dosage form. A freeze-dried dosage form isproduced by forming a dispersion of a gas and a suspension of a bulkforming agent and the enteric coated active ingredient. The bulk formingagent includes such materials as long chain polymers, e.g. polypeptidessuch as gelatin or hydrolyzed gelatin, cellulose derivatives, alginatederivatives, polyvinylpyrrolidone, polyethylene glycols, polysacharridessuch as dextrin, mannitol, sugars and starches, and gums such as acacia,xanthan, and tragacanth. Surfactants such as sodium lauryl sulfate,polyoxyethylene sorbitan esters, sorbitan esters, lecithin, sodiumdioctylsulphosuccinate and other conventionally used surfactants may beadded to the solution or suspension to stabilize the foam formed duringthe dispersion phase. Other optional ingredients may be added to thesolution or suspension such as acidulants, sweeteners, colorants orflavors. The solution or suspension may be dispensed into preformedmolds, cavities or packaging; or deposited in a drop-like fashion inorder to form the tablets. The resulting solution or suspension is thenfreeze dried by a conventional freeze drying process. These tabletsdissolve rapidly in the oral cavity upon ingestion.

Specific embodiments of the present invention are illustrated by way ofthe following examples. This invention is not confined to the specificlimitations set forth in these examples, but rather to the scope of theappended claims. Unless otherwise stated, the percentages and ratiosgiven below are by weight.

Example for Aspirin Chewable Containing Enteric Coated Crystals Example1 Preparation of Enteric Release Coating Solution

A coating dispersion is prepared by dispersing Methyl citrate andanionic copolymer of methacrylic acid and methacrylates (Eudragit L-30D)under ambient conditions, so that the finished dispersion contains 31.6%by weight of the coating materials. The relative amounts of coatingmaterials are, based upon the total weight percent of the final coating,

Triethyl Citrate  7.4% Eudragit L-30D* (30% Solid dispersion) 92.6%*available from Rohm Pharma, Inc.

Example 2 Preparation of Coated Active Ingredient

Preparation of Coated Aspirin: 5000.0 g of aspirin crystals are coatedwith the enteric release solution described in Example 1 at a spray rateof about 70-83 g/min in a Glatt GPCG-5/9 fluid bed unit with a top-sprayinsert under product temperature conditions of about 32-35° C. and anatomization air pressure of 3 bar. The resulting coated aspirin contain,based upon the total dry weight of the coated aspirin and the entericrelease coating, about 35% of the enteric release coating.

Example 3 Production of Tablets for Evaluation Thereof

Preparation of the Tablet Blend Base

Percent Ingredients (w/w) mg/tab Coated Aspirin (65% active) 16.36126.00 Saccharin NF 0.52 4.00 Crospovidone NF 1.65 12.70 Orange Flavor0.52 4.00 Stearic Acid NF 1.97 15.20 Dextrose Monohydrate NF 78.90607.50 Lake Color 0.08 0.60 TOTAL 100.0 770.00

The materials in the table above are blended using the followingprocedure. All materials are manually passed through a 30 mesh screen.The materials are placed into a 4-quart V-Blender and mixed for 5minutes.

Preparation of Compressed Tablets

To prepare the chewable tablet, the tablet base blend is compressed on arotary tablet press. The tablets are compressed at a weight of 770 mgwith a hardness range of 3-9 kiloponds.

Example 4 Analysis of Dissolution Data

All dissolutions for aspirin are analyzed using the followingdissolution analysis: USP Type I apparatus (baskets, 100 RPM) in 0.1Nhydrochloric acid solution (acid stage) at 37° C. for 120 minutes and atpH 6.8 phosphate buffer (buffer stage) at 37° C. for an additional 90minutes. Approximately 20 mL samples are tested at 120 minutes in theacid stage and at an additional 90 minutes in the buffer stage foraspirin quantity. Dissolution samples are analyzed for aspirin versus astandard prepared at the theoretical concentration for 10% released forthe acid stage timepoint and 100% released for the buffer stagetimepoint. Samples are analyzed using a Agilent® UV spectrophotometerset at a wavelength of 280 nm for the acid stage using a 3 cm flow-cell,and at a wavelength of 265 nm for the buffer stage using a 1 cmflow-cell.

We claim:
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 14. A processfor preparing a chewable tablet comprising applying an enteric coatingonto aspirin particles and compressing said enteric-coated aspirinparticles into tablet form.
 15. A process according to claim 14, whereinthe enteric coating is formed from water-soluble or water dispersibleacrylic polymers.
 16. A process according to claim 15 wherein theenteric coating is formed from a solution containing an anioniccopolymer derived from polymethacrylic acid and acrylic acid esters. 17.A process according to claim 14 wherein the enteric coating is formedfrom an aqueous solution having a solids content of at least 20% byweight of a water-soluble or water dispersible acrylic polymer.
 18. Aprocess according to claim 14 wherein the enteric coating weight gain isat least 20%.